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Ivermectin, Hydroxychloroquine, and the Dangers of Scientific Preprints

photograph of "In Evidence We Trust" protest sign

There is a new drug of choice among those who have refused to get vaccinated for COVID-19, or are otherwise looking for alternative treatments: ivermectin, an antiparasitic drug that is used primarily in farm animals. The drug recently made headlines in the U.S. after a judge in Ohio ordered a hospital to treat a patient with it, and a number of countries in Latin America and Europe have begun using it, as well. It is not the first time that a drug that was developed for something else entirely was touted as the new miracle cure for COVID-19: hydroxychloroquine, an anti-malarial, was an early favorite for alternative treatments from former president Trump, despite the FDA’s statement that it had no real effect on patients with COVID-19, and indeed could be very dangerous when used improperly. The FDA has recently issued a statement to a similar effect when it comes to ivermectin, warning that the drug can be “highly toxic in humans.”

It is not surprising that there has been continued interest in alternative treatments to COVID-19: given the existence of vaccine skepticism and various surrounding conspiracy theories, people who do not trust the science of vaccinations, for one reason or another, will look for other ways of fighting the disease. What is perhaps surprising is why this particular drug was chosen as the new alternative treatment. There is, after all, no seemingly good reason to think that a horse de-wormer would be effective at killing the coronavirus. So where did this idea come from?

Not, it turns out, from nowhere. As was the case with hydroxychloroquine, the U.S.-based health analytics company Surgisphere produced a study that purported to show that ivermectin was effective at treating COVID-19, albeit in just “a handful of in vitro and observational studies.” The study was not published in any peer-reviewed outlet, but was instead uploaded as a preprint.

A preprint is a “version of a scientific manuscript posted on a public server prior to formal review”: it’s meant to be a way of rapidly disseminating results to the scientific community at large. Preprints can have significant benefits when it comes to getting one’s results out quickly: peer-review can be a lengthy process, and during a global pandemic, time is certainly of the essence. At the same time, there are a number of professional and ethical considerations that surround the use of preprints in the scientific community.

For example, a recent study on preprints released during the pandemic found a “remarkably low publication rate” for sampled papers, with one potential explanation being that “some preprints have lower quality and will not be able to endure peer-reviewing.” Others have cautioned that while the use of preprints has had positive effects in the physical sciences, when it comes to the medical sciences there is potentially more reason to be concerned: given that developments in medical science is typically of much more interest to the general public, “Patients may be exposed to early, unsubstantiated claims relevant to their conditions, while lacking the necessary context in which to interpret [them].” Indeed, this seems to be what happened with regards to alternative treatments for COVID-19, which have been uploaded online amongst an explosion of new preprint studies.

Additional problems arise when it comes to the use of medical preprints in the media. Another recent study found that while online media outlets linking to preprints was a common practice, said preprints were often framed inconsistently: media outlets often failed to mention that the preprints had not been peer reviewed, instead simply referring to them as “research.” While the authors of the study were encouraged that discussions of preprints in the media could foster “greater awareness of the scientific uncertainty associated with health research findings,” they were again concerned that failing to appropriately frame preprint studies risked misleading readers into thinking that the relevant results were accepted in the scientific community.

So what should we take away from this? We have seen that there are clearly benefits to the general practice of publishing scientific preprints online, and that in health crises in particular the rapid dissemination of scientific results can result in faster progress. At the same time, preprints making claims that are not adequately supported by the evidence can get picked up by members of the general public, as well as the media, who may be primarily concerned with breaking new “scientific discoveries” without properly contextualizing the results or doing their due diligence in terms of the reliability of the source. Certainly, then, there is an obligation on the part of media outlets to do better: given that many preprints do not survive peer review, it is important for the media to note that, when they do refer to preprint studies, that the results are provisional.

It’s not clear, though, whether highlighting the distinction would make much of a difference in the grand scheme of things. For instance, in response to the FDA’s statement that there is no scientific basis for studying the effects of ivermectin on COVID-19, Kentucky senator Rand Paul stated that it was really a “hatred for Trump” that stood in the way of investigating the drug, and not, say, the fact that the preprint study did not stand up to scientific scrutiny. It seems unlikely that, for someone like Paul, the difference between preprints and peer-reviewed science is a relevant one when it comes to pushing a political narrative.

Nevertheless, a better understanding of the difference between preprints and peer-reviewed science could still be beneficial when helping people make decisions about what information to believe. While some preprints certainly do go on to pass peer review, if the only basis that one has for some seemingly implausible medical claims is a preprint study, it is worth approaching those claims with skepticism.

Hydroxychloroquine and the Ethical Pitfalls of Private Science

A box of hydroxychloroquine sulphate tablets held by a hand with coronavirus written in background

Last week, news broke that a significant study into the effects of hydroxychloroquine for treating COVID-19 relied on data that has now been called into question. The effects of this study, and other studies that relied on data from the same source, were profound, leading to changes in planned studies and in treatments for COVID-19 being prescribed to patients. The fact that this data comes from an unaudited source highlights the ethical concerns that stem from having an increased corporate role in science.

In late May, a study published in the elite medical journal The Lancet suggested that COVID-19 patients taking chloroquine or hydroxychloroquine were more likely to die. The study included over 96,000 patients, relying on electronic health data from the company Surgisphere run by Dr. Sepan Desai, who was also included as a co-author of the article. It found that at 671 hospitals where COVID-19 patients had been prescribed hydroxychloroquine, the risk of death was over twice as great as patients who were not prescribed the drug. An additional study using data from Surgisphere investigated the uses of blood pressure medication and was published in a paper for The New England Journal of Medicine. A third paper using Surgisphere data was available as a preprint which suggested that ivermectin significantly reduced mortality in COVID-19 patients. All three papers have been retracted.

The retractions occurred after discrepancies were noticed in the data. The reported doses of hydroxychloroquine for American patients was higher than FDA guidelines and the number of Australian deaths were higher than official statistics. There was also a discrepancy between the small number of hospitals included and the vast number of patient records. Following this, independent auditors were asked to review the data provided by Surgisphere; however, the company refused to provide the data, citing confidentiality requirements with the hospitals. Yet investigations found that no hospitals located in the US admitted to participating with Surgisphere. 

Surgisphere itself is also a suspect source. The company was founded in 2007 but has little online presence. Their website does not list partner hospitals or identify its scientific advisory board. It claims that the company has 11 employees. Their enormous database doesn’t seem to have been used by peer reviewed studies until May. Desai himself also has a colorful history, including a record of three outstanding medical malpractice suits against him. 

The studies had significant impact world-wide. Following the report that hydroxychloroquine increased mortality rates in patients, the WHO announced a “temporary” pause into their studies of hydroxychloroquine (they have since resumed their efforts). The studies also played a role in the national conversation about the drug in the United States following President Trump’s announcement that he had been taking it to combat the virus. The preprint on ivermectin was never officially published, but it did lead to changes in treatment protocols in South America. In Bolivia, a local government planned to hand out 350,000 doses of the drug after receiving authorization from the Bolivian Ministry of Health. The drug was also cited as a potential treatment in Chile and Peru. 

This episode highlights several general moral issues. Retraction scandals at a time when the public is looking to, and relying on, medical science are dangerous. The situation is intensified by the fact that these controversies are tied to the political debate over hydroxychloroquine, as it may undermine science along partisan lines. Polls show that Democrats are far more likely than Republicans to have a great deal of confidence in scientists to act in the best interests of the public yet such scandals further undermine public trust and make science seem more partisan. 

The matter also raises ethical issues within the sciences. According to Ivan Oransky from Retraction Watch, the case represents larger systematic issues within the sciences, noting that even leading journalists rely too heavily on an honor system. For example, the pandemic has led to warning signs about the use of preprints in journals, which have moved away from getting feedback while studies are being finalized to sharing “breaking data” as fast as possible, despite the lack of peer review.  

The Surgisphere episode highlights the ethical pitfalls of science relying on private sector companies for research. Since the twentieth century, the private sector has been an increasing source of scientific funding. In the United States, private funding accounts for 65% of research and development spending in 2013. There are good reasons for private sector investments and corporate-university level partnerships. The public sector has shown less willingness to supply the needed funding. As Ashtosh Jogalekar points out in an article for Scientific American, investments by private interests have allowed for many projects to be funded which might not be funded otherwise. He notes, “For these billionaires a few millions of dollars is not too much, but for a single scientific project hinging on the vicissitudes of government funding it can be a true lifeline.” It has also been noted that private funding can ensure cost-effective replication studies are possible, especially important since efforts to produce reproducibility were only successful in 40% of experiments published in peer-reviewed journals. 

On the other hand, according to Sheldon Krimsky, the author of Science in the Private Interest: Has the Lure of Profits Corrupted Biomedical Research?, numerous problems can occur when scientists partner with private corporations. Krimsky finds that publication practices have been influenced by commercial interests: the commercialization of science has led to a decline in the notion that scientists should work in the public interest, and sharing data becomes more problematic given the use of paywalls and intellectual property protection. This makes it more difficult to verify the data.

There are many ways corporations can complicate data-sharing. By choosing not to release unflattering findings or claiming data as exclusive intellectual property, companies can make it difficult for others to use research (consider Diamond v Chakrabarty which began the precedent for allowing genetically modified organisms to be patentable). And, of course, the Surgisphere episode is an example of university-level researchers working in collaboration with a private company where the company retains sole control of the data. Such cases allow for fraud and suffer from a lack of oversight. 

One proposed solutions is to move towards “open science,” making publications, data, and other information open and accessible to everyone. Such a move would allow for both increased transparency and accountability as well as more rigorous peer-review. Under such a system, falsified data would be more difficult to provide and more easy to detect. 

While many of these issues have been brewing for years, it is not every day that a single published study can have the kind of global impact that came with investigations into the effectiveness of hydroxychloroquine, even while other independent studies have also demonstrated its ineffectiveness. The ethical fallout from this scandal is thus far more obvious given public interest in the disease. Indeed, there have already been calls to stop private speculation into COVID-19 research; part of this call includes the position that all intellectual property should be made available for free to the international scientific community for fighting the pandemic. The question now is what specific reforms should be implemented to prevent scandals like this from happening again?